Although lung transplant rejection has traditionally been thought to occur as a result of host adaptive immune responses to alloantigens present in the donor lung, the lung is unique among transplanted organs in its constant exposures to environmental stimuli and in its intrinsic innate host defenses. Toll-like receptors (TLRs) expressed on pulmonary cells provide the first line of host defense against foreign pathogens and environmental challenges. Our preliminary results demonstrate that polymorphisms of TLR4, which diminish innate responsiveness, also diminish susceptibility to the development of acute rejection. These TLR4 polymorphisms also lead to a reduction in the severity of bronchiolitis obliterans syndrome (BOS), a condition of chronic allograft rejection associated with airflow obstruction and airway obliteration. Based on these observations we hypothesize that activation of innate immunity through TLRs in the transplanted lung promotes the adaptive alloimmune response that leads to acute rejection and BOS. Further support for this hypothesis is provided by the observation that aerosolized challenge with lipopolysaccharide (IPS), a prototypic trigger of innate immunity, leads to the development of pathological lesions of acute rejection and lymphocytic bronchiolitis in mice that have undergone allogenic bone marrow transplant (BMT). In this project we will specifically test the hypothesis that polymorphisms in human TLRs and in related genes transcriptionally activated by LPS regulate the innate response to lung transplant and determine susceptibility to acute rejection and BOS in the following aims: Aim 1 will identify polymorphic variants in TLRs and related innate molecules. Aim 2 will identify polymorphic variations in human candidate genes derived experimentally from differential gene expression studies of LPS induced lung rejection in mice. Aim 3 will genotype 800 lung transplant recipients and their donors for polymorphic variants in candidate genes. Aim 4 will determine if allelic variants in candidate genes among lung transplant recipients or their donors significantly alters the risk for acute rejection or BOS. Completion of these aims will significantly increase our understanding of innate immune regulation of lung transplant rejection and will provide a basis for the development of innovative therapeutic strategies to prevent lung transplant rejection. This project will interact with all cores and include investigations of the TLRs (activated by hyaluronic acid, Project 3) and surfactant proteins A and D (Project 1) in regulating the development of lung transplant rejection.